The present invention relates to a novel L-ascorbic acid 2-phosphate salt, a process for manufacturing the salt and a method of use thereof. More specifically, the present invention relates to L-ascorbic acid 2-phosphate zinc salt or a salt hydrate of zinc L-ascorbic acid 2-phosphate (hereinafter, unless otherwise indicated, the salt including the salt hydrate thereof is referred to as an xe2x80x9cL-ascorbic acid 2-phosphate zinc saltxe2x80x9d) which is a soluble L-ascorbic acid 2-phosphate salt having improved stability. L-ascorbic acid 2-phosphate zinc salt does not cause an extreme alkaline condition on dissolving in water and also exhibits antimicrobial activity. The present invention also relates to a method for manufacturing the salt and a method of use thereof. By using this salt, an L-ascorbic acid 2-phosphate-containing preparation (e.g., a cosmetic preparation, medical preparation, agricultural chemical preparation, animal drug preparation, foodstuff preparation and feedstuff preparation) having improved solubility, stability and antimicrobial properties (including antiseptic, deodorizing and antidandruff effects) and which is stable under weakly acidic conditions, can be obtained.
L-Ascorbic acid (vitamin C) imparts many physiological effects. For example, vitamin C restrains lipid peroxide, accelerates the formation of collagen, retards the formation of melanin and enhances immune functions, and has hitherto been used to achieve these effects in the fields of medicine, agricultural chemicals, animal drugs, foodstuffs, feedstuffs and cosmetic preparations. Many preparations containing L-ascorbic acid are commercially available. However, L-ascorbic acid has poor aging stability, and the effect of vitamin C cannot be always obtained even if such a preparation is used.
In order to improve stability, derivatives obtained by converting the hydroxyl groups in the enediol moiety at the 2- or 3-position each into a glycosyl group (for example, JP-A-5-117290 (the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d)) or into a phosphoric acid ester (for example, JP-B-52-18191 (the term xe2x80x9cJP-Bxe2x80x9d as used herein means an xe2x80x9cexamined Japanese patent publicationxe2x80x9d) and JP-A-2-279690) have been proposed.
However, L-ascorbic acid 2-glycoside salts are converted into L-ascorbic acid in vivo (particularly in humans) at a low rate as compared with L-ascorbic acid 2-phosphates. Therefore, a prompt effect cannot be achieved and an adequately high vitamin C effect can hardly be obtained.
L-Ascorbic acid 2-phosphates provide a prompt effect, and an adequately high vitamin C effect can be easily obtained. However, conventionally known L-ascorbic acid 2-phosphates are a magnesium salt, a calcium salt and a sodium salt, and among these salts, L-ascorbic acid 2-phosphate magnesium salt having excellent stability does not have sufficiently high solubility in water and is difficult to form into an aqueous solution having a concentration of 30% or more. The calcium salt scarcely dissolves in water.
Sodium L-ascorbic acid 2-phosphate having satisfactorily improved solubility can be easily formed into an aqueous solution having a concentration of about 30%, but does not have a stability that is comparable with that of the magnesium salt. Furthermore, when dissolving any of these salts, the pH of the resulting solution is in an alkaline region of approximately from 8 to 10. When the pH is adjusted to a weakly acidic condition, the stability is disadvantageously lowered.
Although the above-described L-ascorbic acid derivatives have been proposed, an L-ascorbic acid 2-phosphate having excellent solubility and which is sufficiently stable even under weakly acidic conditions has not yet been obtained.
In obtaining a salt in general, neutralization of an acid or base is used in many cases. However, this method is not appropriate for manufacturing an L-ascorbic acid 2-phosphate salt on an industrial scale. This is because an L-ascorbic acid 2-phosphate solution is strongly acidic and unstable.
It is therefore an object of the present invention to provide an L-ascorbic acid 2-phosphate having excellent solubility and which exhibits sufficiently improved stability even under weakly acidic conditions.
Under these circumstances, the present inventors have conducted extensive investigations and as a result, have found that hitherto unknown L-ascorbic acid 2-phosphate zinc salt is a compound having highly improved solubility and stability even under weakly acidic conditions, and also provides an antimicrobial (antiseptic) effect.
The above object of the present invention has been achieved by providing L-ascorbic acid 2-phosphate zinc salt and a salt hydrate of zinc L-ascorbic acid 2-phosphate which, in addition to the above properties, has also been found to have an antimicrobial effect. The present invention further provides a process for manufacturing the L-ascorbic acid 2-phosphate zinc salt and salt hydrate thereof and a method of using the salt and salt hydrate thereof in cosmetic and medical preparations, agricultural chemical preparations, animal drug preparations, foodstuff preparations and feedstuff preparations so as to increase the action of vitamin C or to provide an antimicrobial, antiseptic, deodorizing or antidandruff effect.
Examples of the process for manufacturing the compound of the present invention include a manufacturing process starting from a soluble L-ascorbic acid 2-phosphate salt and using an ion exchange technique or the like, and a combination of this manufacturing process with other purification methods, as needed. However, the present invention is by no means limited thereto.
If L-ascorbic acid 2-phosphoric acid is represented by ApH3, the zinc salt of the present invention is represented by Ap2Zn3 and has a structure as shown in formula (1) below: 
Ap2Zn3 is white powder and can be obtained as an anhydrite or salt hydrate. The salt hydrate is considered to be a hydrate Ap2Zn3.nH2O of Ap2Zn3.
In a preferred embodiment of the L-ascorbic acid 2-phosphate zinc salt or salt hydrate thereof of the present invention, 95 mol % or more of the entire cationic charge constitutes zinc ion and 95 mol % or more of the entire anionic charge constitutes L-ascorbic acid 2-phosphate ion. The Zn cation and Ap anion are present in sufficient amounts if each is contained in total in the above-described amounts. For example, when Ap2Zn3 is present in an amount of 95 mol % or more of the total L-ascorbic acid 2-phasphate salt content, Ap2Zn2Mg or the like may be present in part. However, this is acceptable if the zinc ion content is 95 mol % or more of the total cation content.
The L-ascorbic acid 2-phosphate zinc salt of the present invention may be manufactured by a process using, for example, a soluble L-ascorbic acid 2-phosphate salt other than the zinc salt, such as Ap2Mg3, as a starting material and replacing the magnesium with zinc by chemical reaction or using an ion exchange technique (e.g., treating with an ion exchange resin). This process may also be combined with a purification method. Examples of the chemical reaction include:
Ap2Mg3+3ZnCl2xe2x86x92Ap2Zn3+3MgCl2
In a manufacturing process using an ion exchange technique, the soluble L-ascorbic acid 2-phosphate salt used as a starting material is not necessarily purified, but may be, for example, an L-ascorbic acid 2-phosphate-containing solution obtained by reacting L-ascorbic acid with phosphorus oxychloride. The ion exchange step may employ, for example, cation exchange column chromatography or anion exchange chromatography.
When using cation exchange column chromatography, an aqueous L-ascorbic acid 2-phosphate zinc salt solution may be eluted by passing an L-ascorbic acid 2-phosphate solution through a column containing a zinc type cation exchange resin (preferably a strong cationic exchange resin).
In the case of using anion exchange chromatography, a solution containing L-ascorbic acid 2-phosphate is passed through the anion exchange resin column to adsorb L-ascorbic acid 2-phosphate ion onto the resin, a zinc salt solution is passed therethrough, and the L-ascorbic acid 2-phosphate zinc salt fraction is collected.
In the case where the L-ascorbic acid 2-phosphate solution that is added to the column contains a substance which forms a zinc salt having low solubility, the solution is previously processed to remove such substances (for example, in the case of phosphorus ion, a zinc salt or magnesium salt is added to precipitate and remove the substance). In this manner, the column chromatography can be performed more efficiently.
The chromatography conditions (temperature, flow rate, composition of added solution, concentration, amount of solution, etc.) may be established by taking into account general column chromatography parameters (e.g., column size, physical properties of the resin, exchange capacity, separation capability, viscosity of the added solution, solubility, etc.) well known to those of ordinary skill in the art.
L-ascorbic acid 2-phosphate zinc salt powder can be obtained directly from the above solution containing L-ascorbic acid 2-phosphate zinc salt, or by precipitating or the like in an organic solvent and removing the solvent by spray drying, vacuum drying or freeze drying. When the L-ascorbic acid 2-phosphate zinc salt powder is obtained by precipitating in an organic solvent, the zinc salt added to the column in the anion exchange method preferably, in view of purity, is a salt which is highly soluble in the organic solvent (for example, in the case of using acetone as the organic solvent, zinc chloride or zinc propionate may be used).
The thus-obtained L-ascorbic acid 2-phosphate zinc salt has excellent solubility and is easily formed into an aqueous solution having a concentration of 50 wt % or more. Furthermore, the L-ascorbic acid 2-phosphate zinc salt of the present invention is remarkably stable even under weakly acidic conditions, and a composition containing an L-ascorbic acid 2-phosphate having sufficiently improved stability even in such a pH region can be obtained. Furthermore, a composition also having an antimicrobial effect (including antiseptic, deodorizing and antidandruff effects) can be obtained. Furthermore, vitamin C can be effectively supplied by administering the composition to humans or animals. Examples of the composition include cosmetic preparations, medical preparations, agricultural chemical preparations, animal drug preparations, foodstuff preparations and feedstuff preparations. The ingredients of the composition and the amount of the L-ascorbic acid 2-phosphate zinc salt added thereto are the same as in the case of using a conventional L-ascorbic acid 2-phosphate salt.
For example, a general and preferred range for the content (wt %) of the L-ascorbic acid 2-phosphate zinc salt when added to a cosmetic preparation, a medical preparation, an agricultural chemical preparation, an animal drug preparation, a foodstuff preparation and a feedstuff preparation may be as follows:
In the case of a salt hydrate, the above amounts are increased to take into account the water of hydration.